ERCC1 and ERCC2 variants predict survival in gastric cancer patients.
ABSTRACT: PURPOSE: ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients. EXPERIMENTAL DESIGN: We genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes. RESULTS: We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P=0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P=0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P=0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P=0.011), compared with the common haplotype G-T-G. CONCLUSION: ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.
Project description:A number of studies have investigated the roles of excision repair cross complementation group 1 (ERCC1), ERCC2, and ERCC5 genes polymorphisms in the development of glioma; however, the results were inconsistent. Here, we performed a meta-analysis to investigate the association between 6 polymorphisms in the ERCC genes (rs3212986, rs11615, rs13181, rs1799793, rs238406, rs17655) and glioma risk.The PubMed, Embase, and Web of science were searched up to September 6, 2016, for studies on the association between ERCC polymorphisms and glioma risk. A fixed-effects or random-effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. Sensitivity and cumulative meta-analyses were also performed.A total of 15 studies were eligible for the pooled analysis, conducted in 2 populations of ethnic descent: 8 Europeans and 7 Asians. The results showed that ERCC1 rs3212986 polymorphism was positively associated with glioma [AA vs CC: odds ratio (OR) = 1.298, 95% confidence interval (95% CI) = 1.043-1.230, P?=?.025]. Association of the ERCC2 rs13181 and rs1799793 polymorphisms was only observed in Asians (CC vs AA for rs13181: OR?=?1.539, 95% CI?=?1.122-2.109, P?=?.007; AA vs GG for rs1799793: OR?=?1.474, 95% CI?=?1.090-1.994, P?=?.012). However, no association was observed between glioma risk and ERCC1 rs11615, ERCC2 rs238406, and ERCC5 rs17655 polymorphisms. Moreover, sensitivity and cumulative meta-analyses confirmed the stability of the results.Our meta-analysis indicated that the ERCC1 rs3212986 polymorphism and 2 polymorphisms in ERCC2 gene (rs13181 and rs1799793) contributed to the susceptibility of glioma.
Project description:We conducted a prospective study to analyze whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. A total of 228 patients with pathologically proven gastric cancer and receiving platinum-based chemotherapy were recruited from our hospital between October 2009 and October 2011. The ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 polymorphisms were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Conditional logistic regression analysis revealed that patients carrying the CA and AA genotypes of ERCC1 rs3212986 polymorphism showed a poorer response to chemotherapy compared to the CC genotype (CA vs. CC: OR = 0.28, 95% CI = 0.06-0.98, P = 0.04; AA vs. CC: OR = 0.49, 95% CI = 0.06-0.98, P = 0.01). Moreover, the CA+AA genotype of ERCC1 rs3212986 polymorphism showed a significantly poorer response to chemotherapy (CA+AA vs. CC: OR = 0.49, 95% CI = 0.27-0.90). Patients with the AA genotype of ERCC1 rs3212986 polymorphism had a longer overall survival time when compared with the CC genotype (34.91 months vs. 51.19 months, log-rank P = 0.003). The AA genotype of ERCC1 rs3212986 polymorphism in gastric cancer patients was correlated with a higher risk of death from varying causes by the Cox proportional hazards model, compared to the CC genotype (HR = 6.19, 95% CI = 1.42-30.60). In conclusion, the ERCC1 rs3212986 polymorphism was found to influence the response to chemotherapy and overall survival of gastric cancer patients.
Project description:Benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts are a risk factor for tobacco-related cancers. Excision repair cross-complementing complementation group 1 (ERCC1) and excision repair cross-complementing complementation group 2/xeroderma pigmentosum D (ERCC2/XPD) participate in the nucleotide excision repair (NER) pathway that removes BPDE-DNA adducts; however, few studies have provided population-based evidence for this association. Therefore, we assayed for levels of in vitro BPDE-induced DNA adducts and genotypes of single-nucleotide polymorphisms (SNPs) of the NER genes ERCC1 (rs3212986 and rs11615) and ERCC2/XPD (rs13181, rs1799793 and rs238406) in 707 healthy non-Hispanic whites. The linear trend test of increased adduct values in never to former to current smokers was statistically significant (P(trend) = 0.0107). The median DNA adduct levels for the ERCC2 rs1799793 GG, GA and AA genotypes were 23, 29 and 30, respectively (P(trend) = 0.057), but this trend was not observed for other SNPs. After adjustment for covariates, adduct values larger than the median value were significantly associated with the genotypes ERCC1 rs3212986TT [odds ratio (OR) = 1.89, 95% confidence interval (CI) = 1.03-3.48] and ERCC2/XPD rs238406AA (OR = 0.64, 95% CI = 0.41-0.99) and rs238406CA (OR = 0.63, 95% CI = 0.45-0.89) compared with their corresponding wild-type homozygous genotypes. The results of haplotype analysis further suggested that haplotypes CAC and CGA of ERCC2/XPD, TC of ERCC1 and CACTC of ERCC2/XPD and ERCC1 were significantly associated with high levels of DNA adducts compared with their most common haplotypes. Our findings suggest that the genotypes and haplotypes of ERCC1 and ERCC2/XPD may have an effect on in vitro BPDE-induced DNA adduct levels.
Project description:The aim of the current study was to investigate the role of polymorphisms in DNA repair pathways on the clinical outcome of gastric cancer patients treated with platinum-based chemotherapy. A total of 380 gastric cancer patients treated with platinum-based chemotherapy were included in the present study. The genotypes of ERCC1 rs11615 (Asn118Asn) and rs3212986 (*197G>T), ERCC2 rs1799793 (Asn312Asp) and rs13181 (Lys751Gln), NBN rs1805794 (Gln185Gln) and rs1063054 (*1209A>C), RAD51 rs1801321 (-61G>T) and rs12593359 (*502T>G), and XRCC3 rs861539 (Thr241Met) were determined by polymerase chain reaction-restriction fragment length polymorphism, according to the manufacturer's instructions. The TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 were found to be associated with improved response to chemotherapy, with an adjusted odds ratio of 1.66 (95% CI, 1.07-2.56) and 1.61 (95% CI, 1.05-2.49), respectively. Based on the results of Cox analysis, patients with TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 exhibited a significantly decreased risk of mortality, with hazard ratios of 1.71 (95% CI, 1.06-2.72) and 1.97 (95% CI, 1.28-3.03), respectively. In conclusion, these results suggest that ERCC1 rs11615 and ERCC2 rs1799793 in the DNA repair pathways may be used as predictive factors of the clinical outcome in gastric cancer patients.
Project description:We performed a study to investigate the role of ERCC1, ERCC2, ERCC5, XPA and XPC polymorphisms from perspective of the whole NER pathway in the prognosis of gastric cancer. A total of 410 gastric cancer patients were recruited between January 2010 and December 2011. Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was used to analyze genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs13181 and s1799793, ERCC5 rs17655, XPA rs1800975 and XPC rs2228001. Our study found that carriers of ERCC1 rs3212986 TT genotype showed significantly favorable survival than wide-type GG genotype in multivariate analysis (OR=6.38, 95% CI=2.54-19.03), and patients with variant CC genotype of ERCC2 rs13181 exhibited better response to chemotherapy than those with AA genotype (OR=2.21, 95% CI=1.17-4.25). By Cox proportional hazards model, patients with variant TT genotype of ERCC1 rs3212986 exhibited longer PFS and OS than those who had GG genotype (for PFS, HR=0.37, 95% CI=0.17-0.75; for OS, HR=0.36, 95% CI=0.13-0.87). For ERCC2 rs13181 polymorphism, carriers with CC genotype demonstrated significantly increased hazards of progression of disease and death in multivariate model (for PFS, HR=0.48, 95% CI=0.26-0.88; for OS, HR=0.44, 95% CI=0.20-0.91). In conclusion, our finding suggests that ERCC1 rs3212986 and ERCC2 rs13181 gene polymorphism could influence the response to chemotherapy and clinical outcome of gastric cancer.
Project description:Some previous studies have sought to investigate the roles of excision repair cross complementation group 1 (ERCC1), ERCC2, ERCC4, and ERCC5 gene polymorphisms in the prognosis of osteosarcoma patients. However, their results were inconclusive. Here, we performed a meta-analysis to determine the strength of the association between eight polymorphisms in the ERCC genes (rs11615, rs3212986, rs2298881, rs13181, rs1799793, rs1800067, rs2296147, and rs1047768) and prognosis of osteosarcoma patients treated with chemotherapy.We retrieved the relevant studies from PubMed, Embase, and Web of Science in human osteosarcoma published prior to July 2017. Primary outcomes included overall survival (OS) and event-free survival, expressed by hazard ratios (HRs) with their corresponding 95% CIs. STATA software (version 12.0) was utilized to perform data synthesis.A total of 13 eligible follow-up studies involving 2,303 patients met all the inclusion criteria, conducted in two populations of ethnic descent: 11 Asians and two Caucasians. In the present meta-analysis, we demonstrated that the homozygous variant genotypes in ERCC2 rs1799793 and ERCC5 rs2296147 were significantly associated with OS in osteosarcoma (TT vs GG for rs1799793: HR = 0.62, 95% CI = 0.41-0.93, Pheterogeneity = 0.310, I2 = 15.3%, P = 0.020; TT vs CC for rs2296147: HR = 0.42, 95% CI = 0.23-0.78, Pheterogeneity = 0.708, I2 = 0.0%, P = 0.006). In addition, no evidence of association was observed between prognosis in osteosarcoma and ERCC1 rs11615, ERCC1 rs3212986, ERCC1 rs2298881, ERCC2 rs13181, ERCC4 rs1800067, and ERCC5 rs1047768 polymorphisms.Our meta-analysis indicated that TT genotype in the ERCC2 rs1799793 and ERCC5 rs2296147 might prolong the survival time of patients with osteosarcoma, suggesting that the rs1799793 and rs2296147 polymorphisms can be used as predictors for prognosis of osteosarcoma patients treated with chemotherapy.
Project description:OBJECTIVE:: Several previous studies have reported the role variant of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms in the risk of glioma, but the results of these studies are inconsistent. Therefore, we aimed to conduct a meta-analysis to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 on the risk of glioma. METHODS:A comprehensive research was conducted through the databases of Pubmed, EMBASE and the China National Knowledge Infrastructure (CNKI) platforms until June 1, 2014, including 14 eligible case-control studies. RESULTS:Our meta-analysis found that ERCC1 rs3212986 AA genotype was significantly associated with increased risk of glioma compared with CC genotype, and the pooled OR (95%CI) was 1.29(1.07-1.55). By subgroup analysis, ERCC1 rs3212986 AA genotype was found to be significantly correlated with increased glioma risk in Chinese population (OR=1.37, 95%CI=1.07, 1.55), Similarly, we found that ERCC2 rs13181 GT and TT genotypes were significantly associated with increased risk of glioma in Chinese population, with ORs(95%CI) of 1.47(1.17-1.85) and 1.50(1.02-2.22). But ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms had no significant association with glioma risk in Caucasian populations. By begg's funnel plot, we found that no publication bias was existed in this meta-analysis. CONCLUSION:Our meta-analysis suggested that ERCC1 rs3212986 and ERCC2 rs13181 polymorphism play an important risk factor for brain tumor development in Chinese population, but no association in Caucasian populations.
Project description:OBJECTIVE:To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients. METHODS:Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. RESULTS:Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People's Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73-4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively. CONCLUSION:Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma.
Project description:BACKGROUND: Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair (NER), of which ERCC1 and ERCC2/XPD exert an indispensable role. Genetic variations in ERCC1 and ERCC2 have been related to DNA repair efficiency. In this study we used lymphocytes from healthy individuals to show that polymorphisms in ERCC1 and ERCC2 are directly associated with decreased DNA repair efficiency. METHODS: ERCC1 (rs3212986 and rs11615) and ERCC2 (rs13181, rs1799793 and rs238406) were genotyped in 818 healthy Han individuals from the northeast of China. BPDE induced DNA adducts in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 282 randomly selected participants. The effect of ERCC1 rs3212986 and ERCC2 rs238406 on DNA damage caused by B[a]P was assessed with a modified comet assay. RESULTS: We found that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 were associated with the high levels of BPDE-DNA adducts. Especially ERCC1 rs3212986 A-allele variant was significantly associated with the high BPDE-DNA adducts. Haplotype analysis showed that the ERCC1 haplotype AC (OR?=?2.36, 95% CI?=?1.84-2.97), ERCC2 haplotype AGA (OR?=?1.51, 95% CI?=?1.06-2.15) and haplotype block AGAAC (OR?=?5.28, 95% CI?=?2.95-9.43), AGCAC (OR?=?1.35 95% CI?=?1.13-1.60) were linked with high BPDE-DNA adducts. In addition, we found that the combined minor alleles of ERCC1 rs3212986 and ERCC2 rs238406 were associated with a reduced DNA repair capacity. CONCLUSIONS: Our results suggest that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 are associated with decreased repair efficiency of BPDE induced DNA damage, and may be predictive for an individual's DNA repair capacity in response to environmental carcinogens.
Project description:Genetic variability of DNA repair mechanisms influences chemotherapy treatment outcome of gastric cancer. We conducted a cohort study to investigate the role of ERCC1-ERCC2 gene polymorphisms in the chemotherapy response and clinic outcome of gastric cancer. Between March 2011 and March 2013, 228 gastric patients who were newly diagnosed with histopathology were enrolled in our study. Genotypes of ERCC1 rs11615, rs3212986, rs2298881 and ERCC2 rs3212986 were conducted by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. We found that individuals carrying TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 were associated with better response to chemotherapy and longer survival time of gastric cancer. Moreover, individuals with AA genotype of ERCC2 rs1799793 were correlated with shorter survival of gastric cancer. In conclusion, ERCC1 rs11615, rs2298881 and ERCC2 rs1799793 polymorphism play an important role in the treatment outcome of gastric cancer.